The present invention relates to the use of pharmaceutical compositions for inhibiting the production or blocking the action of Tumor Necrosis Factor xcex1 (TNF-xcex1), and for preventing or alleviating diseases and conditions associated with this cytokine, such as septic shock or cachexia. Said pharmaceutical compositions comprise as their active ingredient the stereospecific (+) enantiomers, having (3S,4S) configuration, of xcex946-tetrahydrocannabinol (THC) type compounds of general formula (I), as defined hereinbelow. 
Tumor necrosis factor alpha (TNF-xcex1) is a pleiotropic cytokine, which has been implicated in inflammatory and immunological responses, as well as in pathogenesis of endotoxic and septic shock (reviewed by Tracey and Cerami, Ann. Rev. Med. 45, 491-503, 1994; Glauser et al. Clin. Infect Dis. 18, suppl. 2, 205-216, 1994). TNF is one of several cytokines released mainly by mononuclear phagocytic cells in response to various stimuli. Though the role of cytokines in pathophysiological states has not been fully elucidated, it appears that TNF-xcex1 is a major mediator in the cascade of injury and morbidity.
Among the serious disease states related to the production of TNF-xcex1, a partial list includes the following: septic shock; endotoxic shock; cachexia syndromes associated with bacterial infections (e.g., tuberculosis, meningitis), viral infections (e.g., AIDS), parasite infections (e.g., malaria), and neoplastic disease; autoimmune disease, including some forms of arthritis (especially rheumatoid and degenerative forms); and adverse effects associated with treatment for the prevention of graft rejection.
Septic shock is an often lethal syndrome associated with the massive release of host cytokines due to stimuli present on, or released by, invasive micro-organisms. These invasive stimuli induce polyclonal stimulation of the infected host immune system, and include both lipopolysaccharide (LPS), an endotoxin that stimulates B-cells and macrophages, and superantigens which are exotoxins that stimulate T-cells.
Septic shock has been recognized generally as a consequence of gram-negative bacterial infection, but it is now clear that it can also result from infection with gram positive micro-organisms and probably also by fungi, viruses and parasites. The microorganism itself, its components or products trigger the host cells, especially the macrophages, to release inflammatory mediators such as TNF-xcex1, thereby initiating a cascade of events leading to cachexia, sepsis syndrome and septic shock. TNF-xcex1 is a major mediator initiating septic shock, and therefore stands out as a potential therapeutic target (Lynn and Cohen, Clin. Infect. Dis. 20, 143-158, 1995).
Despite vast improvements in intensive care and antibiotic therapy, septic shock remains associated with a very high rate of mortality (30 to 90%). The poor prognosis for this syndrome is due to the fact that this severe complication of infection results in multiple organ failure, even when the actual infection itself is successfully treated. It is, therefore, apparent that effective therapies for this syndrome are an unmet medical need.
Various therapies have been suggested for the treatment of septic shock syndrome, but as yet none of these has proven to be clinically efficacious. Antibodies against TNF-xcex1 prevent the detrimental effects of superantigen (Miethke et al., J. Exp. Med. 175, 91-98, 1992) or LPS (Beutler et al., Science 229, 869-871, 1985). The use of anti-TNF antibodies to treat septic shock is disclosed for example in WO 92/16553 (Centocor Inc.). WO 92/01472 (Celltech Ltd.) discloses a multivalent immunoglobulin used to treat diseases associated with elevated cytokine levels. Various cytokines that inhibit TNF secretion can also reduce the toxicity of LPS action (Tzung et al., Eur. J. Immunol. 22, 3097-3101, 1992; Gerard et al., J. Exp. Med. 177, 547-550, 1993).
Soluble forms of the TNF binding protein (TBP) (Nophar et al. EMBO J., 9, 3269-3278, 1990) may prevent the action of TNF by preventing binding to its receptors.
Specific classes of compounds have been suggested for the treatment of diseases associated with elevated TNF or other inflammatory mediators, as disclosed for example in WO 95/11014 (Searle and Co.); WO 95/09627, WO 95/09624 and WO 95/09623 (Smith-Kline Beecham Corp.); WO 95/09619 (Wellcome Found.); WO 95/03051 (Pharmacia AB); WO 95/01980 (Pfizer Inc.); EP 629401 (Bayer AG); WO 93/14082 (SmithKline Beecham Corp.); and WO 89/05145 (Hoechst Roussel Pharm Inc.).
None of these disclosures is relevant to the present invention, which deals with a class of compounds developed as non-psychotropic analogs of tetra-hydrocannabinol (THC), the active ingredient of marijuana. Some of the compounds of general formula (I) are disclosed in U.S. Pat. Nos. 4,179,517 and 4,876,276 and 5,284,867. As disclosed in said U.S. patents, these essentially pure synthetic (+)-(3S,4S)-THC derivatives and analogues are devoid of any undesired cannabimimetic psychotropic side-effects. These known compounds have been described as having analgesic, antiemetic, antiglaucoma and neuroprotective activity.
According to the present invention, it is now disclosed that the said known compounds, as well as some novel compounds, in addition to having said analgesic, antiemetic, neuroprotective and anti-glaucoma activity, are unexpectedly also effective against the diseases and conditions mentioned above, by virtue of their ability to block the production or action of TNF-xcex1.
The present invention provides pharmaceutical compositions for reducing and even preventing morbidity and mortality associated with the production of TNF-xcex1, or other cytokines. The present compositions are also effective in alleviating other cytokine induced damage including the wasting or cachexia associated with AIDS, tuberculosis, neoplasia or trauma, and may prevent or ameliorate other disease states associated with the production of cytokines, including malaria and parasitic infections.
The compositions of the present invention are also effective in the treatment of certain chronic degenerative diseases including arthritis and other autoimmune afflictions which are characterized by production of TNF-xcex1. In this connection, the compositions of the present invention are contemplated as therapeutically effective in the treatment of multiple sclerosis. In addition, the present compositions can be administered to a patient who exhibits the symptoms associated with cachexia due to acquired immune deficiency syndrome, neoplasia, trauma or other wasting syndromes, as well as to those having other autoimmune diseases.
The present invention relates to pharmaceutical compositions for the purposes set out above, in which the active ingredient is a compound of the general formula I: 
having the (3S,4S) configuration and being essentially free of the (3R,4R) enantiomer, wherein A - - - B indicates an optional 1(2) or 6(1) double bond,
R is
(a) xe2x80x94Q wherein Q is a heterocyclic moiety having a labile hydrogen atom so that said moiety acts as a carboxylic acid analogue,
(b) xe2x80x94Rxe2x80x2X wherein Rxe2x80x2 is C1-C5 alkyl and X is halogen, xe2x80x94ORxe2x80x3 wherein Rxe2x80x3 is hydrogen, C1-C5 alkyl, or xe2x80x94OC(O)Rxe2x80x2xe2x80x3 wherein Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl,
(c) xe2x80x94Rxe2x80x2N(Rxe2x80x3)2 wherein Rxe2x80x2 is C1-C5 alkyl and each Rxe2x80x3, which may be the same or different, is hydrogen or C1-C5 alkyl optionally containing a terminal xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94OC(O)Rxe2x80x2xe2x80x3 moiety wherein Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl,
(d) xe2x80x94Rxe2x80x2 wherein Rxe2x80x2 is C2-C5 alkyl,
(e) xe2x80x94Rxe2x80x2ORxe2x80x2xe2x80x3 wherein Rxe2x80x2 is C1-C5 alkyl and Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl, or
(f) xe2x80x94Rxe2x80x2xe2x80x94C(O)ORxe2x80x2xe2x80x3, wherein Rxe2x80x2xe2x80x3 may be absent and Rxe2x80x2 and Rxe2x80x2xe2x80x3 are as defined above;
G is (a) halogen, (b) C1-C5 alkyl, or (c) xe2x80x94OR1 wherein R1 is (axe2x80x2) xe2x80x94Rxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-C5 alkyl optionally containing a terminal xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94OC(O)Rxe2x80x2xe2x80x3 moiety wherein Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl, or (bxe2x80x2) xe2x80x94C(O)Rxe2x80x2xe2x80x3 wherein Rxe2x80x2xe2x80x3 is as previously defined; and
R2 is (a) C1-C12 alkyl, (b) xe2x80x94ORxe2x80x3xe2x80x3, in which Rxe2x80x3xe2x80x3 is a straight chain or branched C2-C9 alkyl which may be substituted at the terminal carbon atom by a phenyl group, or (c) xe2x80x94(CH2)nORxe2x80x2xe2x80x3 wherein n is an integer of 1 to 7 and Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl.
In a currently preferred group of compounds, R2 designates a 1,1-dimethylalkyl radical or a 1,2-dimethylalkyl radical with a total of at least 7 carbon atoms. Also preferred are precursors of such compounds. Particularly preferred compounds are those wherein R2 is 1,1-dimethylheptyl or 1,2-dimethylheptyl. It is these embodiments of R2 that are found in THC and its analogues. However, for the cytokine-inhibiting activity that characterizes the present invention, it is believed that any lower or mid-range alkyl substituent will be suitable at this position.
The compositions of the present invention are particularly effective in alleviating and even preventing morbidity and mortality associated with the production of TNF-xcex1, or other cytokines. Methods are provided for treatment of diseases associated with the production of TNF-xcex1 by administering to a patient in need thereof a composition comprising as active ingredient a therapeutically effective amount of a compound of general formula I.